Anititumoral ecteinascidin derivatives

Abstract

This invention relates to antitumoral ecteinascidin derivatives that contain a fused ecteinascidin five ring system with a 1,4-bridge having the structure of formula (VIa) or (VIb) as described herein and compounds in which the —NH 2 or —OH of the 1,4-bridge is derivatized, and related pharmaceutical compositions and methods. Such ecteinascidin derivatives include, but are not limited to, those compounds having formula (XVIIb): in which R 1 and R 4 together form a group of formula (VIa) or (VIb) as described herein, and R 5 , R 7 , R 8 , R 14a , R 14b , R 15 , and R 21 are as defined herein.

1. A compound of formula (XVIIb): 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  and R 4  together form a group of formula (VIa) or (VIb): 
 
       
         
           
           
               
               
           
         
       
       wherein the —CHNH 2  in formula (.VIa) is replaced by a group
 CHNH—CO—R a , or the —CHOH group in formula (VIb) is replaced by a group —CHO—CO—R a , wherein R a  is:
 (i) aromatic heterocyclyl; or 
 (ii) partially saturated heterocyclyl; or 
 (iii) completely saturated heterocyclyl; and 
 each of which is optionally substituted with one or more substituents selected from the group consisting of halo, cyano, nitro, carboxyalkyl, alkoxy, aryl, aryloxy, aromatic heterocyclyl, partially saturated heterocyclyl, completely saturated heterocyclyl, aromatic heterocyclyloxy, partially saturated heterocyclyloxy, completely saturated heterocyclyloxy, alkyl, haloalkyl, and amino; 
 R 5  is H, —OH or O-acyl, wherein the acyl group is of formula —CO—R aa , wherein R aa  is alkyl, alkoxy, alkenyl, arylalkyl, aryl, arylalkylene, amino acid, aromatic heterocyclyl, partially saturated heterocyclyl, or completely saturated heterocyclyl, each of which is optionally substituted with one or more substituents selected from the group consisting of halo, cyano, nitro, carboxyalkyl, alkoxy, haloalkoxy, aryl, aryloxy, heterocyclyl, heterocyclyloxy, alkyl, and amino; 
 R 7  is —OCH 3  and R 8  is —OH or R 7  and R 8  together form a group —O—CH 2 —O—; 
 R 14a  and R 14b  are both —H or one is —H and the other is —OH, —OCH 3  or —OCH 2 CH 3 , or R 14a  and R 14b  together form a keto group; 
 R 15  is —H or —OH; 
 R 21  is —H, —OH or —CN, 
 wherein each of aryl and aryloxy, independently, contain 1 to 3 separate or fused rings and from 6 to 18 carbon ring atoms, and wherein each of heterocyclyl and heterocyclyloxy independently contain one, two or three heteroatoms selected from N, O or S atoms, 
 and derivatives where the group —NCH 3  at the 12-position is replaced by —NH or —NCH 2 CH 3 ; or a pharmaceutically acceptable salt thereof. 
 
 
     
     
       2. The compound of  claim 1 , wherein R a  is aromatic heterocyclyl, which is optionally substituted with one or more substituents selected from the group consisting of halo, cyano, nitro, carboxyalkyl, alkoxy, aryl, aryloxy, aromatic heterocyclyl, partially saturated heterocyclyl, completely saturated heterocyclyl, aromatic heterocyclyloxy, partially saturated heterocyclyloxy, completely saturated heterocyclyloxy, alkyl, haloalkyl, and amino. 
     
     
       3. The compound of  claim 1 , wherein R a  is completely saturated heterocyclyl, which is optionally substituted with one or more substituents substituents selected from the group consisting of halo, cyano, nitro, carboxyalkyl, alkoxy, aryl, aryloxy, aromatic heterocyclyl, partially saturated heterocyclyl, completely saturated heterocyclyl, aromatic heterocyclyloxy, partially saturated heterocyclyloxy, completely saturated heterocyclyloxy, alkyl, haloalkyl, and amino. 
     
     
       4. The compound of  claim 1 , wherein R 1  and R 4  together form a group of formula (VIa), wherein the —CHNH 2  in formula (VIa) is replaced by a group —CHNH—CO—R a . 
     
     
       5. The compound of  claim 4 , wherein R a  is aromatic heterocyclyl, which is optionally substituted with one or more substituents substituents selected from the group consisting of halo, cyano, nitro, carboxyalkyl, alkoxy, aryl, aryloxy, aromatic heterocyclyl, partially saturated heterocyclyl, completely saturated heterocyclyl, aromatic heterocyclyloxy, partially saturated heterocyclyloxy, completely saturated heterocyclyloxy, alkyl, haloalkyl, and amino. 
     
     
       6. The compound of  claim 4 , wherein R a  is completely saturated heterocyclyl, which is optionally substituted with one or more substituents substituents selected from the group consisting of halo, cyano, nitro, carboxyalkyl, alkoxy, aryl, aryloxy, aromatic heterocyclyl, partially saturated heterocyclyl, completely saturated heterocyclyl, aromatic heterocyclyloxy, partially saturated heterocyclyloxy, completely saturated heterocyclyloxy, alkyl, haloalkyl, and amino. 
     
     
       7. The compound of  claim 1 , wherein R 5  is —O—CO—R aa . 
     
     
       8. The compound of  claim 7 , wherein R aa  is alkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, arylalkylene, haloalkylarylalkylene, arylalkyl, aryl, aryl-aryl, haloaryl, nitroaryl, alkenyl, aromatic heterocyclyl, partially saturated heterocyclyl, completely saturated heterocyclyl, or amino acid. 
     
     
       9. The compound of  claim 1 , wherein R aa  is alkyl. 
     
     
       10. The compound of  claim 9 , wherein R aa  is CH 3 . 
     
     
       11. The compound of  claim 1 , wherein R 7  and R 8  together form a group —O—CH 2 —O—. 
     
     
       12. The compound of  claim 1 , wherein R 14a  and R 14b  are hydrogen. 
     
     
       13. The compound of  claim 1 , wherein R 15  is hydrogen. 
     
     
       14. The compound of  claim 1 , wherein R 21  is —OH. 
     
     
       15. The compound of  claim 1 , wherein R 21  is —CN. 
     
     
       16. The compound of  claim 1 , wherein:
 R 1  and R 4  together form a group of formula (VIa), wherein the —CHNH 2  in formula (VIa) is replaced by a group —CHNH—CO—R a ; and 
 R 5  is —O—CO—R aa . 
 
     
     
       17. The compound of  claim 16 , wherein R a  is aromatic heterocyclyl, which is optionally substituted with one or more substituents substituents selected from the group consisting of halo, cyano, nitro, carboxyalkyl, alkoxy, aryl, aryloxy, aromatic heterocyclyl, partially saturated heterocyclyl, completely saturated heterocyclyloxy, aromatic heterocyclyloxy, partially saturated heterocyclyloxy, completely saturated heterocyclyloxy, alkyl, haloalkyl, and amino. 
     
     
       18. The compound of  claim 17 , wherein R a  is coumarinyl. 
     
     
       19. The compound of  claim 17 , wherein R a  is pyridinyl, which is optionally substituted with one or more substituents substituents selected from the group consisting of halo, cyano, nitro, carboxyalkyl, alkoxy, aryl, aryloxy, aromatic heterocyclyl, partially saturated heterocyclyl, completely saturated heterocyclyl, aromatic heterocyclyloxy, partially saturated heterocyclyloxy, completely saturated heterocyclyloxy, alkyl, haloalkyl, and amino. 
     
     
       20. The compound of  claim 17 , wherein R a  is pyrazolyl or isoxazolyl, each of which is optionally substituted with one or more substituents substituents selected from the group consisting of halo, cyano, nitro, carboxyalkyl, alkoxy, aryl, aryloxy, aromatic heterocyclyl, partially saturated heterocyclyl, completely saturated heterocyclyl, aromatic heterocyclyloxy, partially saturated heterocyclyloxy, completely saturated heterocyclyloxy, alkyl, haloalkyl, and amino. 
     
     
       21. The compound of  claim 16 , wherein R a  is completely saturated heterocyclyl, which is optionally substituted with one or more substituents substituents selected from the group consisting of halo, cyano, nitro, carboxyalkyl, alkoxy, aryl, aryloxy, aromatic heterocyclyl, partially saturated heterocyclyl, completely saturated heterocyclyl, aromatic heterocyclyloxy, partially saturated heterocyclyloxy, completely saturated heterocyclyloxy, alkyl, haloalkyl, and amino. 
     
     
       22. The compound of  claim 21 , wherein R a  is pyrrolidinyl, which is optionally substituted with one or more substituents substituents selected from the group consisting of halo, cyano, nitro, carboxyalkyl, alkoxy, aryl, aryloxy, aromatic heterocyclyl, partially saturated heterocyclyl, completely saturated heterocyclyl, aromatic heterocyclyloxy, partially saturated heterocyclyloxy, completely saturated heterocyclyloxy, alkyl, haloalkyl, and amino. 
     
     
       23. The compound of  claim 16 , wherein R aa  is alkyl. 
     
     
       24. The compound of  claim 23 , wherein R aa  is CH 3 . 
     
     
       25. The compound of  claim 16 , wherein R 7  and R 8  together form a group —O—CH 2 —O—, and each of R 14a , R 14b , and R 15  is hydrogen. 
     
     
       26. The compound of  claim 16 , wherein R 21  is —OH. 
     
     
       27. The compound of  claim 16 , wherein R 21  is —CN. 
     
     
       28. The compound of  claim 1 , wherein:
 R 1  and R 4  together form a group of formula (VIa), wherein the —CHNH 2  in formula (VIa) is replaced by a group —CHNH—CO—R a , wherein R a  is aromatic heterocyclyl, which is optionally substituted with one or more substituents substituents selected from the group consisting of halo, cyano, nitro, carboxyalkyl, alkoxy, aryl, aryloxy, aromatic heterocyclyl, partially saturated heterocyclyl, completely saturated heterocyclyl, aromatic heterocyclyloxy, partially saturated heterocyclyloxy, completely saturated heterocyclyloxy, alkyl, haloalkyl, and amino; 
 R 5  is —O—CO—R aa , wherein R aa  is alkyl; 
 R 7  and R 8  together form a group —O—CH 2 —O—; 
 each of R 14a , R 14b , and R 15  is hydrogen; and 
 R 21  is —OH or —CN. 
 
     
     
       29. The compound of  claim 28 , wherein R a  is coumarinyl. 
     
     
       30. The compound of  claim 28 , wherein R a  is pyridinyl, which is optionally substituted with one or more substituents substituents selected from the group consisting of halo, cyano, nitro, carboxyalkyl, alkoxy, aryl, aryloxy, aromatic heterocyclyl, partially saturated heterocyclyl, completely saturated heterocyclyl, aromatic heterocyclyloxy, partially saturated heterocyclyloxy, completely saturated heterocyclyloxy, alkyl, haloalkyl, and amino. 
     
     
       31. The compound of  claim 28 , wherein R a  is pyrazolyl or isoxazolyl, each of which is optionally substituted with one or more substituents substituents selected from the group consisting of halo, cyano, nitro, carboxyalkyl, alkoxy, aryl, aryloxy, aromatic heterocyclyl, partially saturated heterocyclyl, completely saturated heterocyclyl, aromatic heterocyclyloxy, partially saturated heterocyclyloxy, completely saturated heterocyclyloxy, alkyl, haloalkyl, and amino. 
     
     
       32. The compound of  claim 1 , wherein:
 R 1  and R 4  together form a group of formula (VIa), wherein the —CHNH 2  in formula (VIa) is replaced by a group —CHNH—CO—R a , wherein R a  is completely saturated heterocyclyl, which is optionally substituted with one or more substituents substituents selected from the group consisting of halo, cyano, nitro, carboxyalkyl, alkoxy, aryl, aryloxy, aromatic heterocyclyl, partially saturated heterocyclyl, completely saturated heterocyclyl, aromatic heterocyclyloxy, partially saturated heterocyclyloxy, completely saturated heterocyclyloxy, alkyl, haloalkyl, and amino; 
 R 5  is —O—CO—R aa  , wherein R aa  is alkyl; 
 R 7  and R 8  together form a group —O—CH 2 —O—; 
 each of R 14a , R 14b , and R 15  is hydrogen; and 
 R 21  is —OH or —CN. 
 
     
     
       33. The compound of  claim 32 , wherein R a  is pyrrolidinyl, which is optionally substituted with one or more substituents substituents selected from the group consisting of halo, cyano, nitro, carboxyalkyl, alkoxy, aryl, aryloxy, aromatic heterocyclyl, partially saturated heterocyclyl, completely saturated heterocyclyl, aromatic heterocyclyloxy, partially saturated heterocyclyloxy, completely saturated heterocyclyloxy, alkyl, haloalkyl , and amino. 
     
     
       34. The compound of  claim 1 , wherein the compound has the formula: 
       
         
           
           
               
               
           
         
       
       wherein R 1 , R 4 , and R 21  are as defined in  claim 1 . 
     
     
       35. The compound of  claim 1 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
     
     
       36. The compound of  claim 1 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
     
     
       37. The compound of  claim 1 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
     
     
       38. The compound of  claim 1 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
     
     
       39. The compound of  claim 1 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
     
     
       40. The compound of  claim 1 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
     
     
       41. The compound of  claim 1 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
     
     
       42. The compound of  claim 1 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
     
     
       43. The compound of  claim 1 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
     
     
       44. The compound of  claim 1 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
     
     
       45. The compound of  claim 1 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
     
     
       46. The compound of  claim 1 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
     
     
       47. A pharmaceutical composition comprising a compound according to  claim 1  or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or diluent.